Immune System Disorders

Introduction

The immune system mainly serves to protect your body from various infections. Its components achieve this goal by being specific for each pathogen, by being mobile to reach all body organs, and by memorizing the antigen to provide future protection. Immune cells possess the ability to replicate themselves to amplify the immune response. Without a healthy immune system, your body is exposed to many pathogens capable of causing severe and fatal infections. Weak or comprised immune systems drastically increase the risk of infections. However, hyperactive or prolonged immune response causes hypersensitivity or allergic reactions. Allergic reactions may be caused by a disease-causing allergen or by any otherwise normal environmental component. Your body can initiate an immune response against your own body cells or tissues, resulting in autoimmune diseases. 

 

Diseases of the Immune System

Diseases such as myasthenia gravis (MG), rheumatoid arthritis (RA), insulin-dependent diabetes mellitus (IDDM), multiple sclerosis (MS), and Lupus (SLE) are known to be caused by the body's autoimmune response. Autoimmune diseases can be treated using immunosuppressive medications such as cyclosporine, azathioprine, and mycophenolate. Immunodeficiency is another disease related to the immune system. 

Acquired immune deficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), is one of the most serious immunodeficiency diseases. HIV is a virus that causes AIDS, a disease that suppresses the body's natural immune system. The virus destroys T lymphocytes (T cells) that fight infections, leaving patients prone to deadly infections. In some cases, the immune system is suppressed using medications to protect against autoimmune diseases and certain cancers. It's also sometimes done to prevent organ rejection after an organ transplant. 

When HIV infection first began spreading in the United States, it was thought to be an exclusive disease among the homosexual male population. Soon thereafter, it became evident that HIV infection was being passed not only between homosexual males, but also through blood transfusions, intravenous drug use, male-to-female sexual contact, female-to-female sexual contact, mother to baby, and exposure in the workplace from patient to healthcare worker.

 

Human Immunodeficiency Virus (HIV) Infection

HIV is most commonly found in blood, semen, and vaginal secretions. The greatest risk factors for contracting HIV infection are participating in unprotected sexual activity and intravenous drug abuse where a needle is shared with an HIV-positive person. The virus can be passed along from the mother to the fetus or from the mother to the infant during delivery. Before 1985, transmission occurred through transfusion of HIV-contaminated blood products, but this form of transmission has virtually stopped due to blood screenings. 

It's important to note that a person can be infected with HIV for years before developing AIDS. During this time, the infected person can unknowingly transmit the virus to others. AIDS is a fatal disease because it's impossible to cure. HIV infection suppresses the immune system so that it can no longer fight diseases and infections, eventually leading to death.

There are treatments available now that may prevent the virus from actually developing into AIDS. Even though these HIV medications may not cure AIDS, they're helping patients to live longer.

During the early stage of HIV infection, the patient experiences mild symptoms such as fever, diarrhea, sore throat, and muscle aches. The ability to fend off diseases remains quite good. 

A mid-stage period of HIV infection is persistent generalized lymphadenopathy, in which enlarged lymph nodes, skin rashes, chronic fatigue, and weight loss occur. Finally, full-blown AIDS strikes, rendering the immune system powerless. The patient becomes subject to opportunistic infections such as Kaposi's sarcoma (KS), Pneumocystis carinii pneumonia (PCP), and lymphoma. 

* Viruses are tricky microorganisms that are constantly changing and reproducing, so new research is always needed for prevention and treatment.

 

The HIV life cycle starts once HIV enters the host blood, where it attacks a specific type of T cells called CD4 cells. HIV binds to the chemokine receptor 5 (CCR5) on the CD4 cell surface. HIV then fuses with the CD4 surface to inject its ribonucleic acid (RNA) into the cell along with other viral proteins necessary for the virus to replicate. The CCR5 receptor is the target of new research on HIV treatment. Fusion inhibitors are also one of the newer class of HIV medications that target the enzyme that helps in fusing HIV to the CD4 cell surface. 

Once inside the CD4 cell, viral RNA is converted into viral deoxyribonucleic acid (DNA) with the help of an enzyme called reverse transcriptase. Many HIV medications, called reverse transcriptase inhibitors, target this enzyme to stop the replication process. Viral DNA then crosses into the cell nucleus and inserts itself into the host DNA with the help of an enzyme called integrase. Another class of HIV medications, called integrase inhibitors, targets this enzyme to halt the virus replication. 

 

Once the viral DNA is incorporated into the host DNA, it starts replicating to produce multiple strands of the new viral RNA. New viral RNA synthesizes its own viral proteins and an immature HIV develops. An enzyme called protease helps in the maturation process of the immature virus. Protease inhibitors are another class of HIV medications, which target HIV replications at this last step of virus multiplication. 

Once HIV takes over the host CD4 cells, it starts replicating to manufacture enough HIV to cause infection and symptoms of the disease. As the number of functional CD4 cells decreases, the body's immune system capability starts decreasing as well. The decrease in the body's functional immune response increases its risk of contracting infections, leading to complications of the disease and, eventually, death if treatment is unable to control the virus multiplication.

 

The following provides a summary of HIV replication:

1. Binding—HIV binds to the CD4 cell surface.

2. Fusion—HIV and CD4 cell membrane fuse.

3. Reverse transcription—HIV, using its enzyme reverse transcriptase, converts its RNA into DNA. DNA then enters the CD4 cell nucleus.

4. Integration—Another HIV enzyme, integrase, facilitates the insertion of the HIV DNA into the CD4 cell DNA.

5. Replication—Now as part of the CD4 DNA, HIV begins to replicate its own RNA and other HIV proteins.

6. Assembly—New HIV RNA, along with other viral proteins, produces an immature HIV.

7. Budding—Immature HIV comes out of the CD4 cell and uses its own enzyme called protease to become a mature and infectious HIV.

 

There are many HIV medications on the market and many more on the horizon. Reverse transcriptase, protease, and integrase have been the target f HIV research for years, and many medications are available that target these enzymes to control the replication of HIV and progression of AIDS. Fusion inhibitors and CCR5 antagonists are the newer targets for the HIV treatment. 

HIV medications are never used as a single drug therapy. HIV is targeted with a combination of 2- ,3- , or even a 4-drug regimen. HIV is a notorious virus that changes its genomic structure rapidly and may develop resistance to the HIV drugs quickly. Combination regimens decrease the risk of resistance to HIV drugs and increases treatment efficacy. It's important for patients to adhere strictly to the prescribed regimen to reduce the risk of resistance and increase the effectiveness of these drugs.

 

HIV drugs that are currently available on the market are listed in the following HIV Medications table. Reverse transcriptase inhibitors are further divided into two classes—nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs)—based on their structure and mechanism of inhibiting the enzyme. Since generic names of HIV medications are long and complex, these medications are commonly referred to by the acronyms given in parentheses next to the generic name, as shown in the HIV Medications tables.

 

           Drug Class: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

 

Mechanism of Action

Exert effect on step 3 of the HIV replication by inhibiting the enzyme reverse transcriptase.

Generic Name                           Brand Name

Abacavir (ABC)                             Ziagen

Didanosine (ddl)                          Videx

Emtricitabine                               Emtriva

Lamivudine (3TC)                        Epivir

Stavudine (d4T)                           Zerit

Tenofovir (TDF)                           Viread

Zidovudine (AZT)                        Retrovir

 

Drug Class: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

 

Mechanism of Action

Exert effect on step 3 of the HIV replication by inhibiting the enzyme reverse transcriptase.

Generic Name                   Brand Name

Delavirdine (DLV)                Rescriptor

Efavirenz (EFV)                     Sustiva

Etravirine (ETR)                   Intelence

Nevirapine (NVP)                Viramune

 

 

Drug Class: Protease Inhibitors (PIs)

 

Mechanism of Action

Exert effect on step 7 of the HIV replication by inhibiting the enzyme protease.

Generic Name

Atazanavir (ATV)

Darunavir (DRV)

Fosamprenavir (FPV)

Indinavir (IDV)

Lopinavir/Ritonavir (LPVr)

Nelfinavir (NFV)

Ritonavir (RTV)

Saquinavir (SQV)

Brand Name

Reyataz

Prezista

Lexiva

Crixivan

Kaletra

Viracept

Norvir

Invirase

 

Drug Class: Fusion Inhibitor

 

Mechanism of Action

Exerts effect on step 2 of the HIV replication.

Generic Name

Enfuvirtide (T20)

Brand Name

Fuzeon

 

Drug Class: CCR5 Antagonist

 

Mechanism of Action

Exerts effect on step 1 of the HIV replication.

Generic Name

Maraviroc 

Brand Name

Selzentry

 

Drug Class: Integrase Inhibitor

 

Mechanism of Action

Exerts effect on step 4 of the HIV replication by inhibiting the enzyme integrase.

Generic Name

Raltegravir (RAL)

Brand Name

Isentress

 

Drug Class: Combination Products

 

Mechanism of Action

Common commercially available combination products of 2 or more medications.

Generic Name

Zidovudine + Lamivudine

Efavirenz + Emtricitabine + Tenofovir

Abacavir + Lamivudine + Zidovudine

Brand Name

Combivir

Atripla

Trizivir

 

 

Highly Active Antiretroviral Therapy (HAART) is a term that refers to the combination of antivirals used to effectively treat HIV infection. Combination regimens of different classes of medication that are proven to be safe and effective are called HAART regimens. HAART regimens improve efficacy as well as reduce HIV resistance. 

 

HIV patients or patients with weaker immune systems are at high risk of serious infections such as opportunistic infections, pneumocystis jirovecii pneumonia (PJP), and mycobacterium avium complex (MAC).

Pneumocystis jirovecii pneumonia (PJP) and mycobacterium avium complex (MAC) are the two common types of opportunistic infections in HIV-infected patients.

Opportunistic infections are infections caused by microorganisms that are otherwise rarely infectious to individuals with good immune systems. HIV-infected patients or patients with weaker immune systems are at high risk of having opportunistic infections. These infections may be fatal for HIV-infected patients.

PJP is a type of lung infection, or pneumonia, caused by a microorganism called Pneumocystis jirovecii. It's the most common and life-threatening infection in HIV-infected patients. PCP prophylaxis with the following medications is recommended for patients with HIV infection;

•  Sulfamethoxazole/Trimethoprim (Bactrim)
• Dapsone (Dapsone)
• Atovaquone (Mepron)
• Pentamidine inhalation (Nebupent)                                                       

MAC is a group of bacteria that can cause serious and deadly infections of the lungs, bones, and blood in HIV patients. MAC infection is generally considered an end-stage complication of AIDS. MAC prophylaxis with the following medications is recommended for patients with HIV infection:

• Azithromycin (Zithromax)
• Clarithromycin (Biaxin)
• Rifabutin (Mycobutin)

 

Organ Transplant Rejection and Immunosuppression 

There are three types of organ rejection based on the time elapse between the organ transplant and the rejection: hyperacute, acute, and chronic. 

Hyperacute rejection occurs within minutes of implanting a new organ. One of the main causes of this type of rejection is mismatched blood type or other markers. Hyperacute rejection usually requires removal of the new organ.

Acute rejection occurs within two or three weeks of the organ transplant. It's a T-cell mediated immune response to specific markers on the donor organ.

Chronic rejection usually occurs after three or more months of the organ transplant. It's a B-cell mediated response that produces antibodies against the donor organ.

 

Immunosuppression is a phenomenon of decreased or total lack of immune response in the body. It may be caused by diseases such as cancer and HIV infection. Immunosuppression may also be induced during an organ transplant and then be continued as maintenance therapy to prevent chronic rejection. Patients on immunosuppressive medications after an organ transplant are at a higher risk of contracting infections. Patients are generally instructed to practice good hand hygiene, avoid close contact with the sick, and stay away from crowded places.

To prevent acute organ rejection, induction immunosuppressive therapy is administered before, during, or immediately after the organ transplant. Induction therapy works by depleting functional lymphocytes to prevent an immediate immune response against the new organ. The following medications are commonly used as induction therapy to eliminate all antibodies against the new organ:

• Antithymocyte globulin (Atgam or ATG, and rATG)
• Muromonab-CD3 (OKT3)
• Anti-interleukin-2 (IL-2)
• Basiliximab (Simulect)

Maintenance Immunosuppression Therapy

Various combinations of immunosuppressive medications are used for continuous immunosuppression to prevent chronic rejection of the new organ. These medications work by suppressing, inhibiting, or decreasing the production of the T cells and B cells. The following medications are commonly used to avoid chronic rejection:

• Cyclosporine (Sandimmune, Neoral)
• Tacrolimus (Prograf)
• Methylprednisolone (Solu-Medrol)
• Prednisone (Prelone)
• Azathioprine (Imuran)
• Mycophenolate (CellCept)

 

Key Points

• The immune system may become weak due to diseases such as HIV infection.
• The immune system may become overactive or hyperactive due to an allergen, resulting in a hypersensitivity reaction. Examples include allergic reaction from a bee sting or taking medications such as sulfa drugs and penicillin.
• Sometimes the immune system stays hyperactive over periods of time due to normal environmental components causing allergies such as seasonal allergy to pollens or grass.
• Your own body cells and tissues can trigger an immune response, causing various autoimmune diseases such as myasthenia gravis, rheumatoid arthritis, and multiple sclerosis.
• HIV infection is the most notorious immune system disease and can expose your body to fatal infections.
• There are many HIV medications that can control the progression of the disease, but there's still no cure for AIDS.